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Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255
Annals of Oncology 11: 1141-1146. 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands.
Original article Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255 S. M. Lichtman,1 D. Niedzwiecki,2 M. Barcos,6 T. L. Carlisle,3 M. R. Cooper,4 J. L. Johnson2 & B. A. Peterson,5 for the Cancer and Leukemia Group B 'Don Monti Division of Oncology, North Shore University Hospital-NYU School of Medicine, Manhasset, New York; 2Department of Biostatistics, Duke University Medical Center, Durham, North Carolina; 3Division of Hematology Oncology, University of Iowa Hospitals, Iowa City, Iowa; 4 Bowman Gray School of Medicine, Winston-Salem, North Carolina; ^ Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 6 Roswell Park Memorial Institute, Buffalo, New York, USA * See Appendix on page 1145 for a list of participating institutions
vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2/day. Cyclophosphamide 750 mg/m2 was Background: Patients with resistant diffuse aggressive non- given as an iv bolus day 6 and prednisone was given at 100 Hodgkin's lymphoma (DA-NHL) have a poor prognosis. mg/day p.o. on days 1-5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR Studies have suggested infusional therapy may be beneficial. Patients and methods: This trial used an infusional regimen 31%). Freedom from progression was 24% at six months and called I-CHOPE in resistant patients who had previously 8% at one year. Survival was 69% at six months and 40% at received only bolus CHOPE or CHOP regimen. Resistance one year. In an exploratory analysis a prior CR or PR prewas defined as: a) primary refractory disease, b) progression dicted response to I-CHOPE. Twelve of sixteen patients who on therapy, c) partial response, d) complete remission lasting had a CR/PR on previous therapy responded while two of less than one year. Eligibility criteria included a diagnosis of thirteen who had no prior response, responded to I-CHOPE DA-NHL (IWF E-H), no prior irradiation and adequate {P = 0.003). The toxicity was tolerable with grade 3-4 hematologic toxicity being leucopenia 94% and thrombocytopenia organ function. 41%. The grade 3-4 non-hematologic toxicities were infection Results: Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology in 28%, phlebitis in 11%, and stomatitis in 15%. (5) and other (3). The median age was 57 years (range 29-81) Conclusions: I-CHOPE can induce responses in this group with 21 males. The performance status scores were: 0 (12 of patients with a poor prognosis, but most were seen in those patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted who had previously had a response to bolus chemotherapy. of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour Key words: CHOPE, infusional therapy, non-Hodgkin's lymcontinuous intravenous infusion of doxorubicin 10 mg/m2/day, phoma, refractory lymphoma, relapsed lymphoma Summary
Introduction
Patients with either resistant or refractory non-Hodgkin's lymphoma require new and more effective treatments to induce a response. The prognosis of patients who fail to achieve remission or who relapse soon after remission is obtained is poor with two year survival rates of about 25% [1]. Some patients with tumors that retain sensitivity to chemotherapy may benefit from high-dose therapy and bone marrow transplantation [2]. The schedule of administration of chemotherapeutic agents is another variable that has been evaluated to a limited extent in lymphomas and may provide an alternative arena for treatment. Since most chemotherapy has been studied using bolus dosing, the continuous infusion of drugs might provide several benefits.
An infusional program provides the opportunity for prolonged exposure of resistant cells to multiple antineoplastic drugs and may increase dose intensity [3-10]. Infusional therapy has been studied as primary therapy for intermediate grade histology non-Hodgkin's lymphoma (e.g., the series of COP-BLAM regimens) and has reportedly reversed clinical resistance by inducing responses in previously refractory patients (infusional EPOCH, CDE) [6, 7, 11]. Based on this experience the current study was initiated. The total dose of each drug in infusional CHOPE was based on standard dose in CHOP [12] and adding etoposide to CHOP a regimen with which CALGB had prior experience [13]. The plan was to treat a uniform group of patients showing a high degree of resistance to a standard bolus regimen to determine whether responses could be obtained in these
1142 poor prognosis patients primarily by altering treatment schedule rather than dose. Patients and methods Patients were required to have histologically documented nonHodgkin's lymphoma of one of the following subtypes according to the International Working Formulation (IWF) [14]: diffuse smallcleaved cell (IWF-E), diffuse mixed (1WF-F), diffuse large-cell (IWF-G), large-cell immunoblastic (IWF-H). Central review of tumor histology was performed (MB). Measurable disease was required. Prior therapy was limited to treatment with standard CHOP, high dose CHOP or bolus CHOPE. The details of these regimens have been reported previously [12, 13, 15]. Patients must have demonstrated some degree of resistance to bolus therapy by one of the following criteria: 1) primary refractory disease, i.e no response 2) progression on therapy, 3) partial response, or 4) complete remission lasting less than one year. In addition, prior therapy must have included less than 400 mg/m2 cumulative dose of doxorubicin and patients were required to have a cardiac ejection fraction < 50%. Therapy consisted of a 120-hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/nr/day. Cyclophosphamide 750 mg/m was given as an i.v. bolus day 6 and predmsone was given at 100 mg/day p.o. on days 1-5. The therapy was administered via a central venous catheter. Recombinant G-CSF was not used routinely. It was initiated on the first cycle in patients with an absolute granulocyte count < 1500/ul due to documented bone marrow involvement and used in all subsequent cycles in an attempt to maintain dose and schedule. G-CSF was also initiated for an episode of neutropenic fever lasting > 3 days and was then continued in subsequent cycles. Dose modification for hematologic toxicity occurred only for episodes of neutropenic fever requiring hospitalization lasting >3 days or for lack of hematologic recovery allowing for full-dose retreatment by day 28. Absolute granulocyte nadir did not determine dose modification in the absence of the previous criteria. Doses of cyclophosphamide, doxorubicin, etoposide, and vincristine were reduced by 25% if hematologic recovery (granulocytes > 1500/ul and/or platelets > 100,000/ul) did not occur by day 28. Patients had a repeat left ventricular ejection fraction performed after cycle 2, at the time of restaging and at completion of therapy. Complete response was defined as the disappearance of all measurable or evaluable disease, signs, symptoms and biochemical changes related to the tumor, for >4 weeks, during which no new lesions appeared. Partial response was defined as a reduction of > 50% in the sum of the products of the perpendicular diameters of all measurable lesions lasting > 4 weeks, during which no new lesions appeared, and no existing lesion was enlarged, when compared with pretreatment measurements. All patients were to receive a minimum of two cycles of therapy unless there was clear progression of disease after the first cycle of treatment. Reassessment was done after the second, fourth, and sixth cycles. Progression was defined as either an increase in the product of two perpendicular diameters of any measured lesion by > 25%, or new areas of disease. Treatment failure was defined as progressive disease, death from any cause, failure to respond (stable disease only), or initiation of nonprotocol treatment. Time to treatment failure was measured from study entry to first evidence of progressive disease or recurrence, time of new treatment in patients in partial response or with stable disease, or death from any cause. Survival was measured from study entry to death from any cause. Time to event distributions were estimated using the product-limit method of Kaplan and Meier [16]. The protocol was approved by the institutional review boards of the participating institutions and all patients provided written informed consent.
Table 1. Patient demographics of eligible patients.
Number of patients Age (in years) Median Range Sex Male Female Race White Hispanic Black Performance status 0 1 2 Symptom stage A B Stage I II III
IV Extranodal sites 0 1 2+ Prior therapy CHOP CHOPE High-dose CHOP
29 57 29-81 21 (72) 8(28) 24 (83) 4(14) 1(3)
12(41) 9(31) 8(28) 16(55) 13(45) 3(10)
6(21) 8(28) 11 (38) 10(35) 9(31) 10(35) 26 (90) 2(7) 1(3)
Results Thirty-seven patients were enrolled on the trial. The patient demographics are listed in Table 1. Eight patients were found to be ineligible. Five of the eight patients had a diagnosis not permitted by the trial. The histologies were follicular small cleaved (B2), follicular large cell (D2), follicular mixed (C2), and two unclassifiable (K5). These patients were not eligible because of concurrent cancer, cardiac ejection fraction less than 40%, and prior complete response lasting greater than three years. All of the patients on this trial were previously treated with standard CHOP therapy except for two patients who were treated with bolus CHOPE and one treated with high dose CHOP [15]. The overall response rate was 48% (CR 17%; PR 31%) with a 95% confidence interval (95% CI) of 30%64% (Table 2). The number of treatment cycles administered ranged from 1-8, with a median of 2 cycles. Of the five patients with a complete response, two received eight cycles of therapy and three received six cycles. Three patients achieved CR after two cycles and two after six cycles. Seven of the nine patients achieving PR obtained their best response after cycle 2. Of the nine patients with a partial response, three received six cycles (one stopping due to progressive disease), four received three cycles (two stopping due to progressive disease, one due to toxicity, and one stopping to go on to autolo-
1143 Table 4. Response intervals.
Table 2. Response rates to infusional chope.
CR PR NR PROG NA
n (%)
95% CI
5(17) 9(31) 8(28) 6(21) 1(3)
3%-31% 14%-48%
Freedom from progresson Overall survival
Six months
Twelve months
Median duration
0.24(0.09-0.40) 0.69(0.52-0.86)
0.08(0.00-0.19) 0.40(0.22-0.58)
1.8 10.9
95% confidence limits in brackets. Table 3. Response to 1-CHOPE based on prior response to chemotherapy.
Table 5 Treatment toxicity (all cycles). Toxicity grade (« = 27)
Response to I-CHOPE
CR/PR NR/PROG/NA All
Response to previous therapy CR/PR (%)
NR/PROG/NA (%)
12(75) 4(25) 16
2(15) 11 (85) 13
All
14 15 29
gous bone marrow transplantation), two received two cycles (one going off for an autologous bone marrow transplant and one withdrew consent for additional treatment and subsequently relapsed). All of the eight patients with no response received two cycles as specified in the protocol. Of the six patients with progression, three received two cycles and three received one cycle. All stopped due to disease progression. In an exploratory analysis, the response to I-CHOPE were analyzed with regard to patients' response to prior chemotherapy (Table 3). A prior complete response or PR predicted response to I-CHOPE. Twelve of sixteen patients who previously had a CR/PR responded to I-CHOPE while only two of thirteen who had not previously responded, responded to I-CHOPE (P = 0.003, Fisher's exact test). All of the five eligible patients who achieved a complete response on this study had previously responded to CHOP (2 prior PR and 3 CR). Of the nine patients with PRs, three had achieved complete response, four PR and one no response and one had progressed on the previous CHOP therapy. One of the patients who achieved a PR had been previously treated with high-dose CHOP. Both of the patients treated previously with a bolus CHOPE regimen achieved a PR. There are only three patients who did not originally receive standard CHOP. Therefore, the data suggests that those most likely to response to I-CHOPE are those who previously responded to chemotherapy. Table 4 summarizes freedom from progression and overall survival. Toxicity was primarily hematologic (Table 5). The nonhematologic toxicity was tolerable. There was no significant cardiac toxicity observed despite prior exposure to doxorubicin. Eight of twenty-nine (28%) patients received the full six to eight cycles of therapy. The remaining patients received one to three cycles and were removed due to inadequate response or toxicity. Twelve patients (41%) experienced episodes of neutropenic fever; four (14%) had more than one episode. Eight
Granulocytes Platelets Hemoglobin Infection Stomatitis Phlebitis
0/1
2
3
4
1 10 4 18 18 25
0 5 9 2 6 0
1 7 13 6 3 3
27 5 2 2 1 0
Represents numbers of patients.
patients (28%) had treatment delays due to toxicity; two (7%) had more than one delay. Six patients (21%) had dose reductions; two (7%) had more than one cycle reduced. Figure 1 shows freedom from progression (median 1.7 months), Figure 2 shows time to treatment failure (median 1.7 months), and Figure 3 overall survival (median 8.7 months). Discussion This study demonstrates that in a patient population specifically selected because of resistance to primary therapy, the infusional regimen CHOPE can induce responses with an overall response rate of 48%. Toxicity was primarily hematologic and the non-hematologic toxicity was tolerable. Unfortunately, the median time to treatment failure of 1.7 months limits the usefulness of the regimen. Patients with refractory or resistant non-Hodgkin's lymphoma have a poor prognosis. There is no standard regimen for patients who fail primary therapy. Patients who are resistant to standard CHOP are often treated with a number of salvage regimens including ESHAP (etoposide, methyl prednisolone, cytarabine, cisplatin), MINE (mesna, ifosfamide, mitoxantrone, etoposide), IMVP (ifosfamide, methotrexate, etoposide) and DHAP (dexamethasone, cytarabine, and cisplatin) [1, 17-19]. Complete response rates range from 10% to 37% with two-year survival rates of about 25% [1]. These and other single institution studies in relapsed or refractory lymphoma have had varying eligibility requirements, making comparisons difficult. The ability of bone marrow transplantation to salvage these individuals is superior to standard therapy but still produces an overall survival of only 53% [20]. The degree of sensitivity
1144
5
10 Months from Study Entry
Eligible Patients
N= 29
Events= 28
Median= 1.81
Figure I. CALGB 9255: freedom from progression.
5
10
Months (ram Study Entry
Eligible Patients
N=29
Events=28
Median=1.81
Figure 2. CALGB 9255: time to treatment failure.
10
20
30
40
60
Months from Study Entry
Eligible Patients
N=29
Events=2S
Figure 3. CALGB 9255: survival.
Median=9.23|
to chemotherapy correlates with prognosis. In a multiinstitutional study of high dose chemotherapy, the actuarial three-year disease-free survival was 0 in the refractory group, 14% in the resistant-relapse group, and 36% in the sensitive-relapse group [20]. It has been suggested that clinical resistance to therapy can be overcome by altering the schedule of drug administration from bolus to prolonged infusion [4, 11]. There have been many studies using infusional regimens as primary therapy for non-Hodgkin's lymphoma [3-5, 7-10]. Determining whether they are as good as or better than bolus schedules requires phase III trials. Infusional therapy has also been studied in relapsed or refractory patients. One such program, the infusional EPOCH regimen has a 71% response rate in previously refractory patients with a 28% probability of being event-free at one year [11]. EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the drugs in this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity was greater than or equal to that achieved in primary treatment regimens for aggressive lymphomas [11]. The infusional regimen CDE (cyclophosphamide, doxorubicin, etoposide) has been evaluated in refractory lymphoma patients [7]. The objective response rate was 52% including 10 patients with a complete response (17%). In patients resistant or refractory to prior therapy the overall response rate was 42%. These studies do not specify the degree of resistance to primary therapy or the disease free interval prior to treatment with the infusional regimen. The criteria employed in this study of a short disease free interval (less than one year) or refractory disease (no complete response, progression on primary bolus therapy) provided a more stringent test of the ability of an infusional regimen to overcome resistance. In addition the CHOPE, EPOCH and CDE regimens differ slightly in schedule and dose. EPOCH and CDE are given over 96 hours. The doses of doxorubicin (EPOCH 40 mg/m2; CDE 50 mg/m2) and etoposide (EPOCH 200 mg/m2 and CDE 240 mg/m2) also vary. CDE gives cyclophosphamide as an infusion while the other regimens given it as a bolus after the completion of the infusion. The EPOCH, CDE, and CHOPE infusion studies have included patients who had not previously received etoposide. Therefore, the results of these studies are somewhat confounded by the known effectiveness of chronic etoposide infusion in lymphoma [8]. But the ability of these regimens to induce responses is still clear. The analysis of the I-CHOPE program does show that a history of chemoresponsiveness is a critical factor in deriving benefit from the program. Patients who were refractory, based on no prior response to bolus therapy, had only a 15% response rate. Therefore the question whether a bolus regimen can overcome a high degree of clinical drug resistance remains in doubt. This infusional regimen can be a foundation of future studies in the
1145 evaluation of therapy for drug resistant patients. This can ported by CA03927; Washington University School of Medicine, include dose-finding studies of the antineoplastic drugs St. Louis, Missouri (N. L. Bartlett. MD). supported by CA77440; Weill Medical College of Cornell University, New York, New York in combination with agents associated with reversing (M. Schuster, MD), supported by CA07968. resistance in vitro as has been done with tamoxifen and bolus CHOPE [21]. A study of infusional CHOPE ± modulator or a comparison of modulators could be performed in a randomized study of CHOPE failures. References Monitoring of pharmacokinetics and in vitro analysis of mdr expression would be important components of such 1. Laport GF, Williams SF. The role of high-dose chemotherapy in a program. patients with Hodgkin's disease and non-Hodgkin's lymphoma. Semin Oncol 1998; 25: 503-17. The trial does provide a basis for using infusional 2. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone chemotherapy in patients who have relapsed or refracmarrow transplantation as compared with salvage chemotherapy tory non-Hodgkin's lymphoma and have had a response in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. to primary chemotherapy. It was well tolerated and was N Engl J Med 1995; 333: 1540-5. 3. Boyd DB, Coleman M, Papish SW et al. COPBLAM III: Infuable to induce responses in approximately half of the sional combination chemotherapy for diffuse large-cell lymphopatients. This tolerability may allow appropriate patients ma. J Clin Oncol 1988; 6: 425-33. to proceed to further salvage with bone marrow trans4. Carrion JR, Garcia Arroyo FR, Salinas P. Infusional chemoplantation though the short freedom from progress limits therapy (EPOCH) in patients with refractory or relapsed lymphothis regimens utility, particularly in previously chemoma. Am J Clin Oncol 1995; 18: 44-6. 5. Molldrem J, Wilson WH. Infusional chemotherapy for non-Hodgtherapy resistant patients.
Acknowledgements The research for CALGB 9255 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (R. L. Schilsky, MD, chairman). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Appendix Participating institutions CALGB Statistical Office, Durham, North Carolina (S. George, MD), supported by CA33601; Christiana Care Health Services, Inc. CCOP, Wilmington, Delaware (I. M. Berkowitz, DO), supported by CA45418; Community Hospital, Syracuse CCOP, Syraceuse, New York (J. Kirschner, MD), supported by CA45389; Dana Farber Cancer Institute, Boston, Massachusetts (G. P. Canellos, MD), supported by CA32291; Green Mountain Oncology Group CCOP, Bennington, Vermont (J. Wallace Jr, MD), supported by CA35091; Mount Sinai Medical Center CCOP, Miami, Miami Beach, Florida (E. Davila, MD), supported by CA45564; Mount Sinai Medical School of Medicine, New York, New York (J. F. Holland, MD), supported by CA04457; North Shore University Hospital, Manhasset, New York (D. R. Budman, MD), supported by CA35279; Rhode Island Hospital, Providence, Rhode Island (A. Leone. MD), supported by CA08025; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, North Carolina (J. N. Atkins, MD), supported by CA45808; SUNY Health Science Center at Syraceuse, Syraceuse, New York (S. L. Graziano, MD), supported by CA21060; University of Alabama Birmingham, Birmingham, Alabama (R. Diasio, MD), supported by CA47545; University of California at San Diego, San Diego, California (S. L. Seagren, MD), supported by CA11789; University of Iowa Hospitals, Iowa City, Indiana (G. H. Clamon, MD), supported by CA47642; University of Maryland Cancer Center, baltimore, Maryland (D. Van Echo, MD), supported by CA31983; University of Minnesota, Minneapolis, Minnesota (B. A. Peterson, MD), supported by CA16450; University of Missouri/Ellis Fischel Cance Center, Columbia, Missouri (M. C. Perry, MD), supported by CA12046; Wake Forest University School of Medicine, Winston-Salem, North Carolina (D. D. Hurd, MD), sup-
kin's lymphoma. Cancer Invest 1997; 15: 465-74. 6. Ran S, Coleman M, Kaufmann T et al. CODBLAM IV chemotherapy for large cell lymphoma: Sequential use of infusional vincristine and bleomycin and 'high-dose' consolidation. Am J Clin Oncol 1997; 20: 90-6. 7. Sparano JA, Wiernik PH, Leaf A, Dutcher JP. Infusional cyclophosphamide, doxorubicin, and etoposide in relapsed and resistant non-Hodgkin's lymphoma: Evidence for a scheduledependent effect favoring infusional administration of chemotherapy. J Clin Oncol 1993; 11: 1071-9. 8. Thompson DS, Hainsworth JD, Hande KR et al. Prolonged administration of low-dose, infusional etoposide in patients with etoposide-sensitive neoplasms: A phase I-11 study. J Clin Oncol 1993; 11: 1322-8. 9. Topilow AA, Guerra OR, Tarantolo SR et al. COP-BLAM multidrug infusion chemotherapies for lymphoma: Results in a community hospital setting. Cancer Invest 1993; 11: 371-8. 10. Laurence J, Coleman M, Allen SL et al. Combination chemotherapy of advanced diffuse histiocytic lymphoma with the sixdrug COP-BLAM regimen. Ann Intern Med 1982, 97: 190-5. 11. Wilson WH, Bryant G, Bates S et al. EPOCH chemotherapy: Toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol 1993; 11: 1573-82. 12. Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993; 328: 1002-6. 13. Parker BA, Petroni GR, Canellos GP et al. Dose-intensified cyclophosphamide (C) and etoposide (E) in CHOP plus E (CHOPE) therapy of diffuse lymphomas (IWF E-H), CALGB 8852 (Meeting abstract). Blood 1994; 84: 384a. 14. The Non-Hodgkin's Lymphoma Pathologic Classification Project. National Cancer Institute sponsored study of classifications of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage. Cancer 1982; 49: 2112-35. 15. Shipp M, Niedzwiecki D, Johnson J et al. High-dose CHOP induction therapy for poor prognosis aggressive NHL (CALGB 9351): FFP differs at high and low accrual institutions. Blood 1998; 92 (10; Suppl 1): 2005a. 16. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81. 17. Velasquez WS, Cabanillas F, Salvador P et al. Effective salvage therapy for lymphoma with cisplatin in combination with highdose ara-C and dexamethasone (DHAP). Blood 1988; 71: 117-22. 18. Velasquez WS, McLaughlin P, Tucker S et al. ESHAP-an effective chemotherapy regimen in refractory and relapsing lymphoma: A four-year follow-up study. J Clin Oncol 1994; 12: 1169-76.
1146 19. Cabamllas F. Ifosfamide combinations in lymphoma. Semin Oncol 1990; 17: 58-62. 20. Philip T, Armitage JO, Spitzer G et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med 1987; 316: 1493-8. 21. Smith DC, Trump DL. A phase I trial of high-dose oral tamoxifen and CHOPE. Cancer Chemother Pharmacol 1995; 36: 65-8.
Received 7 June 2000; accepted 15 June 2000. Correspondence to: S. M. Lichtman, MD North Shore University Hospital Don Monti Division of Oncology 300 Community Drive Manhasset, New York 11030 USA E-mail, [email protected]
Original article Phase II study of infusional chemotherapy with doxorubicin, vincristine and etoposide plus cyclophosphamide and prednisone (I-CHOPE) in resistant diffuse aggressive non-Hodgkin's lymphoma: CALGB 9255 S. M. Lichtman,1 D. Niedzwiecki,2 M. Barcos,6 T. L. Carlisle,3 M. R. Cooper,4 J. L. Johnson2 & B. A. Peterson,5 for the Cancer and Leukemia Group B 'Don Monti Division of Oncology, North Shore University Hospital-NYU School of Medicine, Manhasset, New York; 2Department of Biostatistics, Duke University Medical Center, Durham, North Carolina; 3Division of Hematology Oncology, University of Iowa Hospitals, Iowa City, Iowa; 4 Bowman Gray School of Medicine, Winston-Salem, North Carolina; ^ Department of Medicine, University of Minnesota, Minneapolis, Minnesota; 6 Roswell Park Memorial Institute, Buffalo, New York, USA * See Appendix on page 1145 for a list of participating institutions
vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/m2/day. Cyclophosphamide 750 mg/m2 was Background: Patients with resistant diffuse aggressive non- given as an iv bolus day 6 and prednisone was given at 100 Hodgkin's lymphoma (DA-NHL) have a poor prognosis. mg/day p.o. on days 1-5. G-CSF was allowed for myelosuppression. The overall response rate was 48% (CR 17%; PR Studies have suggested infusional therapy may be beneficial. Patients and methods: This trial used an infusional regimen 31%). Freedom from progression was 24% at six months and called I-CHOPE in resistant patients who had previously 8% at one year. Survival was 69% at six months and 40% at received only bolus CHOPE or CHOP regimen. Resistance one year. In an exploratory analysis a prior CR or PR prewas defined as: a) primary refractory disease, b) progression dicted response to I-CHOPE. Twelve of sixteen patients who on therapy, c) partial response, d) complete remission lasting had a CR/PR on previous therapy responded while two of less than one year. Eligibility criteria included a diagnosis of thirteen who had no prior response, responded to I-CHOPE DA-NHL (IWF E-H), no prior irradiation and adequate {P = 0.003). The toxicity was tolerable with grade 3-4 hematologic toxicity being leucopenia 94% and thrombocytopenia organ function. 41%. The grade 3-4 non-hematologic toxicities were infection Results: Thirty-seven patients were entered and twenty-nine were eligible. Reasons for ineligibility were incorrect histology in 28%, phlebitis in 11%, and stomatitis in 15%. (5) and other (3). The median age was 57 years (range 29-81) Conclusions: I-CHOPE can induce responses in this group with 21 males. The performance status scores were: 0 (12 of patients with a poor prognosis, but most were seen in those patients); 1 (9 patients); 2 (8 patients). Prior therapy consisted who had previously had a response to bolus chemotherapy. of standard CHOP (26 patients), bolus CHOPE (2 patients), high dose CHOP (1 patient). Therapy consisted of a 120 hour Key words: CHOPE, infusional therapy, non-Hodgkin's lymcontinuous intravenous infusion of doxorubicin 10 mg/m2/day, phoma, refractory lymphoma, relapsed lymphoma Summary
Introduction
Patients with either resistant or refractory non-Hodgkin's lymphoma require new and more effective treatments to induce a response. The prognosis of patients who fail to achieve remission or who relapse soon after remission is obtained is poor with two year survival rates of about 25% [1]. Some patients with tumors that retain sensitivity to chemotherapy may benefit from high-dose therapy and bone marrow transplantation [2]. The schedule of administration of chemotherapeutic agents is another variable that has been evaluated to a limited extent in lymphomas and may provide an alternative arena for treatment. Since most chemotherapy has been studied using bolus dosing, the continuous infusion of drugs might provide several benefits.
An infusional program provides the opportunity for prolonged exposure of resistant cells to multiple antineoplastic drugs and may increase dose intensity [3-10]. Infusional therapy has been studied as primary therapy for intermediate grade histology non-Hodgkin's lymphoma (e.g., the series of COP-BLAM regimens) and has reportedly reversed clinical resistance by inducing responses in previously refractory patients (infusional EPOCH, CDE) [6, 7, 11]. Based on this experience the current study was initiated. The total dose of each drug in infusional CHOPE was based on standard dose in CHOP [12] and adding etoposide to CHOP a regimen with which CALGB had prior experience [13]. The plan was to treat a uniform group of patients showing a high degree of resistance to a standard bolus regimen to determine whether responses could be obtained in these
1142 poor prognosis patients primarily by altering treatment schedule rather than dose. Patients and methods Patients were required to have histologically documented nonHodgkin's lymphoma of one of the following subtypes according to the International Working Formulation (IWF) [14]: diffuse smallcleaved cell (IWF-E), diffuse mixed (1WF-F), diffuse large-cell (IWF-G), large-cell immunoblastic (IWF-H). Central review of tumor histology was performed (MB). Measurable disease was required. Prior therapy was limited to treatment with standard CHOP, high dose CHOP or bolus CHOPE. The details of these regimens have been reported previously [12, 13, 15]. Patients must have demonstrated some degree of resistance to bolus therapy by one of the following criteria: 1) primary refractory disease, i.e no response 2) progression on therapy, 3) partial response, or 4) complete remission lasting less than one year. In addition, prior therapy must have included less than 400 mg/m2 cumulative dose of doxorubicin and patients were required to have a cardiac ejection fraction < 50%. Therapy consisted of a 120-hour continuous intravenous infusion of doxorubicin 10 mg/m2/day, vincristine 0.28 mg/m2/day (maximum 0.4 mg/day), and etoposide 48 mg/nr/day. Cyclophosphamide 750 mg/m was given as an i.v. bolus day 6 and predmsone was given at 100 mg/day p.o. on days 1-5. The therapy was administered via a central venous catheter. Recombinant G-CSF was not used routinely. It was initiated on the first cycle in patients with an absolute granulocyte count < 1500/ul due to documented bone marrow involvement and used in all subsequent cycles in an attempt to maintain dose and schedule. G-CSF was also initiated for an episode of neutropenic fever lasting > 3 days and was then continued in subsequent cycles. Dose modification for hematologic toxicity occurred only for episodes of neutropenic fever requiring hospitalization lasting >3 days or for lack of hematologic recovery allowing for full-dose retreatment by day 28. Absolute granulocyte nadir did not determine dose modification in the absence of the previous criteria. Doses of cyclophosphamide, doxorubicin, etoposide, and vincristine were reduced by 25% if hematologic recovery (granulocytes > 1500/ul and/or platelets > 100,000/ul) did not occur by day 28. Patients had a repeat left ventricular ejection fraction performed after cycle 2, at the time of restaging and at completion of therapy. Complete response was defined as the disappearance of all measurable or evaluable disease, signs, symptoms and biochemical changes related to the tumor, for >4 weeks, during which no new lesions appeared. Partial response was defined as a reduction of > 50% in the sum of the products of the perpendicular diameters of all measurable lesions lasting > 4 weeks, during which no new lesions appeared, and no existing lesion was enlarged, when compared with pretreatment measurements. All patients were to receive a minimum of two cycles of therapy unless there was clear progression of disease after the first cycle of treatment. Reassessment was done after the second, fourth, and sixth cycles. Progression was defined as either an increase in the product of two perpendicular diameters of any measured lesion by > 25%, or new areas of disease. Treatment failure was defined as progressive disease, death from any cause, failure to respond (stable disease only), or initiation of nonprotocol treatment. Time to treatment failure was measured from study entry to first evidence of progressive disease or recurrence, time of new treatment in patients in partial response or with stable disease, or death from any cause. Survival was measured from study entry to death from any cause. Time to event distributions were estimated using the product-limit method of Kaplan and Meier [16]. The protocol was approved by the institutional review boards of the participating institutions and all patients provided written informed consent.
Table 1. Patient demographics of eligible patients.
Number of patients Age (in years) Median Range Sex Male Female Race White Hispanic Black Performance status 0 1 2 Symptom stage A B Stage I II III
IV Extranodal sites 0 1 2+ Prior therapy CHOP CHOPE High-dose CHOP
29 57 29-81 21 (72) 8(28) 24 (83) 4(14) 1(3)
12(41) 9(31) 8(28) 16(55) 13(45) 3(10)
6(21) 8(28) 11 (38) 10(35) 9(31) 10(35) 26 (90) 2(7) 1(3)
Results Thirty-seven patients were enrolled on the trial. The patient demographics are listed in Table 1. Eight patients were found to be ineligible. Five of the eight patients had a diagnosis not permitted by the trial. The histologies were follicular small cleaved (B2), follicular large cell (D2), follicular mixed (C2), and two unclassifiable (K5). These patients were not eligible because of concurrent cancer, cardiac ejection fraction less than 40%, and prior complete response lasting greater than three years. All of the patients on this trial were previously treated with standard CHOP therapy except for two patients who were treated with bolus CHOPE and one treated with high dose CHOP [15]. The overall response rate was 48% (CR 17%; PR 31%) with a 95% confidence interval (95% CI) of 30%64% (Table 2). The number of treatment cycles administered ranged from 1-8, with a median of 2 cycles. Of the five patients with a complete response, two received eight cycles of therapy and three received six cycles. Three patients achieved CR after two cycles and two after six cycles. Seven of the nine patients achieving PR obtained their best response after cycle 2. Of the nine patients with a partial response, three received six cycles (one stopping due to progressive disease), four received three cycles (two stopping due to progressive disease, one due to toxicity, and one stopping to go on to autolo-
1143 Table 4. Response intervals.
Table 2. Response rates to infusional chope.
CR PR NR PROG NA
n (%)
95% CI
5(17) 9(31) 8(28) 6(21) 1(3)
3%-31% 14%-48%
Freedom from progresson Overall survival
Six months
Twelve months
Median duration
0.24(0.09-0.40) 0.69(0.52-0.86)
0.08(0.00-0.19) 0.40(0.22-0.58)
1.8 10.9
95% confidence limits in brackets. Table 3. Response to 1-CHOPE based on prior response to chemotherapy.
Table 5 Treatment toxicity (all cycles). Toxicity grade (« = 27)
Response to I-CHOPE
CR/PR NR/PROG/NA All
Response to previous therapy CR/PR (%)
NR/PROG/NA (%)
12(75) 4(25) 16
2(15) 11 (85) 13
All
14 15 29
gous bone marrow transplantation), two received two cycles (one going off for an autologous bone marrow transplant and one withdrew consent for additional treatment and subsequently relapsed). All of the eight patients with no response received two cycles as specified in the protocol. Of the six patients with progression, three received two cycles and three received one cycle. All stopped due to disease progression. In an exploratory analysis, the response to I-CHOPE were analyzed with regard to patients' response to prior chemotherapy (Table 3). A prior complete response or PR predicted response to I-CHOPE. Twelve of sixteen patients who previously had a CR/PR responded to I-CHOPE while only two of thirteen who had not previously responded, responded to I-CHOPE (P = 0.003, Fisher's exact test). All of the five eligible patients who achieved a complete response on this study had previously responded to CHOP (2 prior PR and 3 CR). Of the nine patients with PRs, three had achieved complete response, four PR and one no response and one had progressed on the previous CHOP therapy. One of the patients who achieved a PR had been previously treated with high-dose CHOP. Both of the patients treated previously with a bolus CHOPE regimen achieved a PR. There are only three patients who did not originally receive standard CHOP. Therefore, the data suggests that those most likely to response to I-CHOPE are those who previously responded to chemotherapy. Table 4 summarizes freedom from progression and overall survival. Toxicity was primarily hematologic (Table 5). The nonhematologic toxicity was tolerable. There was no significant cardiac toxicity observed despite prior exposure to doxorubicin. Eight of twenty-nine (28%) patients received the full six to eight cycles of therapy. The remaining patients received one to three cycles and were removed due to inadequate response or toxicity. Twelve patients (41%) experienced episodes of neutropenic fever; four (14%) had more than one episode. Eight
Granulocytes Platelets Hemoglobin Infection Stomatitis Phlebitis
0/1
2
3
4
1 10 4 18 18 25
0 5 9 2 6 0
1 7 13 6 3 3
27 5 2 2 1 0
Represents numbers of patients.
patients (28%) had treatment delays due to toxicity; two (7%) had more than one delay. Six patients (21%) had dose reductions; two (7%) had more than one cycle reduced. Figure 1 shows freedom from progression (median 1.7 months), Figure 2 shows time to treatment failure (median 1.7 months), and Figure 3 overall survival (median 8.7 months). Discussion This study demonstrates that in a patient population specifically selected because of resistance to primary therapy, the infusional regimen CHOPE can induce responses with an overall response rate of 48%. Toxicity was primarily hematologic and the non-hematologic toxicity was tolerable. Unfortunately, the median time to treatment failure of 1.7 months limits the usefulness of the regimen. Patients with refractory or resistant non-Hodgkin's lymphoma have a poor prognosis. There is no standard regimen for patients who fail primary therapy. Patients who are resistant to standard CHOP are often treated with a number of salvage regimens including ESHAP (etoposide, methyl prednisolone, cytarabine, cisplatin), MINE (mesna, ifosfamide, mitoxantrone, etoposide), IMVP (ifosfamide, methotrexate, etoposide) and DHAP (dexamethasone, cytarabine, and cisplatin) [1, 17-19]. Complete response rates range from 10% to 37% with two-year survival rates of about 25% [1]. These and other single institution studies in relapsed or refractory lymphoma have had varying eligibility requirements, making comparisons difficult. The ability of bone marrow transplantation to salvage these individuals is superior to standard therapy but still produces an overall survival of only 53% [20]. The degree of sensitivity
1144
5
10 Months from Study Entry
Eligible Patients
N= 29
Events= 28
Median= 1.81
Figure I. CALGB 9255: freedom from progression.
5
10
Months (ram Study Entry
Eligible Patients
N=29
Events=28
Median=1.81
Figure 2. CALGB 9255: time to treatment failure.
10
20
30
40
60
Months from Study Entry
Eligible Patients
N=29
Events=2S
Figure 3. CALGB 9255: survival.
Median=9.23|
to chemotherapy correlates with prognosis. In a multiinstitutional study of high dose chemotherapy, the actuarial three-year disease-free survival was 0 in the refractory group, 14% in the resistant-relapse group, and 36% in the sensitive-relapse group [20]. It has been suggested that clinical resistance to therapy can be overcome by altering the schedule of drug administration from bolus to prolonged infusion [4, 11]. There have been many studies using infusional regimens as primary therapy for non-Hodgkin's lymphoma [3-5, 7-10]. Determining whether they are as good as or better than bolus schedules requires phase III trials. Infusional therapy has also been studied in relapsed or refractory patients. One such program, the infusional EPOCH regimen has a 71% response rate in previously refractory patients with a 28% probability of being event-free at one year [11]. EPOCH chemotherapy was well tolerated and highly effective in patients who were resistant to or relapsed from the same drugs administered on a bolus schedule, suggesting that continuous infusion of the drugs in this regimen is capable of partially reversing drug resistance and reducing toxicity. Dose-intensity was greater than or equal to that achieved in primary treatment regimens for aggressive lymphomas [11]. The infusional regimen CDE (cyclophosphamide, doxorubicin, etoposide) has been evaluated in refractory lymphoma patients [7]. The objective response rate was 52% including 10 patients with a complete response (17%). In patients resistant or refractory to prior therapy the overall response rate was 42%. These studies do not specify the degree of resistance to primary therapy or the disease free interval prior to treatment with the infusional regimen. The criteria employed in this study of a short disease free interval (less than one year) or refractory disease (no complete response, progression on primary bolus therapy) provided a more stringent test of the ability of an infusional regimen to overcome resistance. In addition the CHOPE, EPOCH and CDE regimens differ slightly in schedule and dose. EPOCH and CDE are given over 96 hours. The doses of doxorubicin (EPOCH 40 mg/m2; CDE 50 mg/m2) and etoposide (EPOCH 200 mg/m2 and CDE 240 mg/m2) also vary. CDE gives cyclophosphamide as an infusion while the other regimens given it as a bolus after the completion of the infusion. The EPOCH, CDE, and CHOPE infusion studies have included patients who had not previously received etoposide. Therefore, the results of these studies are somewhat confounded by the known effectiveness of chronic etoposide infusion in lymphoma [8]. But the ability of these regimens to induce responses is still clear. The analysis of the I-CHOPE program does show that a history of chemoresponsiveness is a critical factor in deriving benefit from the program. Patients who were refractory, based on no prior response to bolus therapy, had only a 15% response rate. Therefore the question whether a bolus regimen can overcome a high degree of clinical drug resistance remains in doubt. This infusional regimen can be a foundation of future studies in the
1145 evaluation of therapy for drug resistant patients. This can ported by CA03927; Washington University School of Medicine, include dose-finding studies of the antineoplastic drugs St. Louis, Missouri (N. L. Bartlett. MD). supported by CA77440; Weill Medical College of Cornell University, New York, New York in combination with agents associated with reversing (M. Schuster, MD), supported by CA07968. resistance in vitro as has been done with tamoxifen and bolus CHOPE [21]. A study of infusional CHOPE ± modulator or a comparison of modulators could be performed in a randomized study of CHOPE failures. References Monitoring of pharmacokinetics and in vitro analysis of mdr expression would be important components of such 1. Laport GF, Williams SF. The role of high-dose chemotherapy in a program. patients with Hodgkin's disease and non-Hodgkin's lymphoma. Semin Oncol 1998; 25: 503-17. The trial does provide a basis for using infusional 2. Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone chemotherapy in patients who have relapsed or refracmarrow transplantation as compared with salvage chemotherapy tory non-Hodgkin's lymphoma and have had a response in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. to primary chemotherapy. It was well tolerated and was N Engl J Med 1995; 333: 1540-5. 3. Boyd DB, Coleman M, Papish SW et al. COPBLAM III: Infuable to induce responses in approximately half of the sional combination chemotherapy for diffuse large-cell lymphopatients. This tolerability may allow appropriate patients ma. J Clin Oncol 1988; 6: 425-33. to proceed to further salvage with bone marrow trans4. Carrion JR, Garcia Arroyo FR, Salinas P. Infusional chemoplantation though the short freedom from progress limits therapy (EPOCH) in patients with refractory or relapsed lymphothis regimens utility, particularly in previously chemoma. Am J Clin Oncol 1995; 18: 44-6. 5. Molldrem J, Wilson WH. Infusional chemotherapy for non-Hodgtherapy resistant patients.
Acknowledgements The research for CALGB 9255 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (R. L. Schilsky, MD, chairman). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Appendix Participating institutions CALGB Statistical Office, Durham, North Carolina (S. George, MD), supported by CA33601; Christiana Care Health Services, Inc. CCOP, Wilmington, Delaware (I. M. Berkowitz, DO), supported by CA45418; Community Hospital, Syracuse CCOP, Syraceuse, New York (J. Kirschner, MD), supported by CA45389; Dana Farber Cancer Institute, Boston, Massachusetts (G. P. Canellos, MD), supported by CA32291; Green Mountain Oncology Group CCOP, Bennington, Vermont (J. Wallace Jr, MD), supported by CA35091; Mount Sinai Medical Center CCOP, Miami, Miami Beach, Florida (E. Davila, MD), supported by CA45564; Mount Sinai Medical School of Medicine, New York, New York (J. F. Holland, MD), supported by CA04457; North Shore University Hospital, Manhasset, New York (D. R. Budman, MD), supported by CA35279; Rhode Island Hospital, Providence, Rhode Island (A. Leone. MD), supported by CA08025; Southeast Cancer Control Consortium Inc. CCOP, Goldsboro, North Carolina (J. N. Atkins, MD), supported by CA45808; SUNY Health Science Center at Syraceuse, Syraceuse, New York (S. L. Graziano, MD), supported by CA21060; University of Alabama Birmingham, Birmingham, Alabama (R. Diasio, MD), supported by CA47545; University of California at San Diego, San Diego, California (S. L. Seagren, MD), supported by CA11789; University of Iowa Hospitals, Iowa City, Indiana (G. H. Clamon, MD), supported by CA47642; University of Maryland Cancer Center, baltimore, Maryland (D. Van Echo, MD), supported by CA31983; University of Minnesota, Minneapolis, Minnesota (B. A. Peterson, MD), supported by CA16450; University of Missouri/Ellis Fischel Cance Center, Columbia, Missouri (M. C. Perry, MD), supported by CA12046; Wake Forest University School of Medicine, Winston-Salem, North Carolina (D. D. Hurd, MD), sup-
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Received 7 June 2000; accepted 15 June 2000. Correspondence to: S. M. Lichtman, MD North Shore University Hospital Don Monti Division of Oncology 300 Community Drive Manhasset, New York 11030 USA E-mail, [email protected]